The mission of the Mayo M.D.-Ph.D. program is to train talented and enthusiastic students as physician scientists with advanced skills in both biomedical research and academic medicine. Specifically, we wish to prepare students for careers in basic, translational or clinical research studying fundamental questions whose answers will provide new insights into critical health problems. An MSTP grant for the Mayo M.D.- Ph.D. program was first awarded by NIGMS in 2003. During the first four years of support, our MST program has continued to develop and mature while maintaining all of the aspects that were praised by the Reviewers of the prior submission. The main strengths of our MST program are: (1) An enthusiastic training faculty of 75 mentors that provides extensive opportunities for cutting-edge interdisciplinary training in basic, translational, and clinical research; (2) Outstanding students, with 8 trainees supported by this grant over the past 5 years and a total of 47 trainees currently associated with the program, who are passionate about the study of fundamental biological processes of relevance to human disease; (3) A diverse pool of >150 highly competitive applicants; (4) An autonomous admissions process that enables selection of students based on their prior research experiences and excitement for biomedical research; (5) An effective underrepresented minority (URM) student recruitment and retention plan with 4 URM students who completed training during the past five years and 9 in training; (6) Integration of medical and graduate school curricula, which allows students to complete 4 required graduate courses and 3 laboratory rotations during the first two years of medical school; (7) Several programmatic features that respond to specific needs of M.D.-Ph.D. trainees, especially during the first two years of medical school training and the subsequent graduate school years; (8) Continuing institutional support for education, which enables us to fully fund our students throughout their medical and graduate training, providing exceptional flexibility in choosing mentors and thesis laboratories; (9) Exceptional research resources that are accessible to our students and profoundly enhance their educational experience; (10) A dedicated Director and Associate Director and outstanding administrative support for the program. We propose to build on these strengths and continue to train medical scientists who will be well equipped to advance the study of human diseases.